Neural tube defects (NTDs) are serious congenital malformations that are associated with significant morbidity and mortality. In consideration of the emotional burden and lifetime cost of treatment for NTDs, extensive research has been undertaken to understand the mechanisms underlying neural tube development and how various exposures can perturb this highly regulated process. However, the specific factors that contribute to the development of NTDs remain largely unknown. This prospective epidemiological study will examine the hypotheses that NTD risk is associated with maternal exposure to inorganic arsenic (Asi) and that this association may be modified by nutritional or genetic factors. The study will be conducted in a region of northern China that is characterized by both exposure to Asi and a high rate of NTDs. The study will employ a novel hybrid design that combines case-control and family-based aspects and provides improved power relative to either of the component approaches. This study will employ traditional epidemiological methods molecular genetic approaches and and biomarkers of exposure in a unique study population and, hence, provides a unique opportunity to increase our understanding of the causes of NTDs. Such an understanding is required both for improved reproductive counseling and the development of improved population-based preventive strategies. Defects of the brain and spine, NTDs, are one of the most common birth defects, and often result in stillbirth, neonatal death, or lifelong disability. While the cause of these defects is unclear, it is likely that genetics and environmental exposures play a part. This study will investigate these causes in a population that has both a very high rate of NTDs, and exposure to arsenic, a suspected chemical cause of NTDs.